Mental health symptoms among those affected by Huntington's disease: A cross‐sectional study

Abstract Background Although cognitive and motor symptoms of Huntington's disease (HD) are associated with disease progression, the underlying causes of psychological symptoms are not as clearly understood. Recent evidence suggests that some mental health difficulties experienced by people with HD are shared by noncarriers within HD families. Accordingly, there is a need to evaluate potential systemic contributors to HD mental distress, to support meaningful interventions for psychological symptoms in people with HD and affected families. Method We used short‐form Problem Behaviors Assessment mental health symptom data from the international Enroll‐HD data set to characterize mental health symptoms across eight HD groups: Stages 1–5, premanifest and genotype‐negative individuals, and family controls (n = 8567) using chi‐square analysis with post hoc comparisons. Results We identified that people with later‐stage HD (Stages 2–5) had significantly higher apathy, obsessive–compulsiveness, and (from Stage 3) disorientation than the remaining groups at a medium effect size, and that these findings largely held across three measure administrations over time. Conclusions These findings highlight the critical symptoms in manifest HD from Stage 2 onward, but also demonstrate that crucial symptoms such as depression, anxiety, and irritability are present across HD‐affected groups (including noncarriers of the gene expansion). The outcomes highlight a need for specific clinical management of later‐stage HD psychological symptoms, and for systemic support across affected families.

symptoms and presenting increasingly significant challenges to mental health as the condition progresses (Duff et al., 2007;Paulsen, 2011).
Although neural degeneration is believed responsible for many physical and psychological symptoms of HD (Martinez-Horta et al., 2016), there has been less consideration of psychosocial contributors to HD-related mental health. In particular, given the genetic nature of HD, symptoms occur within a family context, and there are systemic stressors affecting those with and without the gene expansion. Developing our understanding of these less-examined factors underlying HD distress is crucial for informing interventional approaches. In this study, we seek to characterize key mental health symptoms arising across the time course of HD (premanifest and Stages 1-5). We also compare these symptoms with people affected by HD who do not carry the gene expansion (genotype-negative and family control individuals), to determine the contribution of systemic factors to HD-related distress. Exploring these issues will contribute to evidence-based therapies for specific needs in particular HD groups, including interventions to systemically support HD families.

Cognitive and emotional changes in HD
Clinical diagnosis of "manifest" HD is based on the presence of motor signs such as chorea, rigidity, and bradykinesia. However, other changes begin up to 15 years before motor symptom onset. These include cognitive changes in memory, executive function, information processing, and emotional lability, and mental health symptoms such as depression, anxiety, irritability/anger, obsessive-compulsive behaviors, apathy, perseveration, and (less commonly) psychosis (Rickards et al., 2011;van Duijn, 2017;van Duijn et al., 2007van Duijn et al., , 2014. Although motor changes are viewed as the most characteristic symptoms of HD, both people with HD (pwHD) and their families report that mental health is a primary issue in care (Mahmood et al., 2022;Smith et al., 2015), and mental distress has been demonstrated throughout HD families, including genetically unaffected individuals (Achenbach & Saft, 2021;Maltby et al., 2021).
The neurodegeneration of striatal and cortical circuits is believed to be responsible for emotional and behavioral symptoms in pwHD (Martinez-Horta et al., 2016). Suggested mechanisms include cingulate cortex degeneration affecting depressive symptoms, emotional recognition and visual working memory, and primary motor cortex cell loss affecting motor function (Hobbs et al., 2011;Thu et al., 2010). Microstructural changes in frontal, cingulate cortical, insula, and cerebllar regions have also been linked with subthreshold depressive symptoms (Sprengelmeyer et al., 2014). However, there is considerable variation in the presentation of the emotional and behavioral symptoms among pwHD and most of these symptoms (anxiety, depression, irritability/anger, and psychosis) have been reported as either unlinked or weakly linked to progression of cognitive and motor changes (Paulsen et al., 2001;Van Duijn et al., 2013;Zappacosta et al., 1996), except for apathy that carries a demonstrated link with HD progression (Martinez-Horta et al., 2016;van Duijn et al., 2014).

Psychosocial contributors to HD symptoms
An alternative approach suggests a psychosocial contribution to HDrelated mental health, alongside biological neurodegeneration. The impact of HD on families can significantly affect mental health across gene-expansion carriers and noncarriers. For example, both groups typically experience disrupted family dynamics, loss of relatives to HD, and changes to expectations about family roles and the future (Berrios et al., 2002;Brouwer-DudokdeWit et al., 2002;Yu et al., 2019). There may also be fears about passing on HD to children, worries about care needs, disability and death in the future, and hypervigilance to potential signs of HD progression (Mahmood et al., 2022;Tibben et al., 1997;Wieringa et al., 2021). "Genotype-negative" individuals who were genetically at risk but have tested negative may also continue to experience distress and intrusive thoughts relating to HD (Tibben et al., 1997 Any potential impacts of social influences on HD-related mental health symptoms can be explored by comparing pwHD (manifest and premanifest) against noncarriers who may be psychologically and socially affected by HD-related stressors (family controls who were not at genetic risk, and genotype-negative individuals who were at risk but tested negative). This enables the identification of symptoms unique to pwHD and those shared by other relevant HD populations.
One recent exploration (Maltby et al., 2021) of underlying structures of psychological distress in HD populations identified four latent factors across manifest and premanifest HD, family control, and genotypenegative groups, comprising symptoms relating to depression, anxiety, temper, and self-harm. No significant differences in anxiety levels were identified between pwHD and control groups, and few mental health differences were found between people with manifest HD and family controls (although the manifest group reported higher depression, temper, and self-harm than the genotype-negative group). Overall, the findings suggested some important commonalities and differences in the structure and severity of mental health symptoms between pwHD and associated populations. However, these findings explored commonalities across broad domains (depression, anxiety, irritability), rather than considering specific clinical symptoms. Individual symptoms such as obsessive-compulsive behaviors, apathy, disorientation, perseveration, and psychosis may reflect key cognitive changes in memory, executive function, information processing, and emotional lability resulting from HD progression, and consequently exploration between HD-affected groups at a symptom level is warranted.

Study aims
To improve our understanding of potential mechanisms underlying HD distress and to inform approaches to medical, pharmaceutical, and psychological interventions, it is important to characterize patterns of mental health symptoms across pwHD and related populations. To this end, we used the international Enroll-HD data set to evaluate type and severity of mental health symptoms across HD stages and in related groups. We aimed to identify mental health symptoms unique to HD, and when in the disease course these occur, as well as examining which symptoms are shared within wider HD family systems. Importantly, we also evaluated replicability of findings across three timepoints, which is rare in the literature.

Sample
Anonymized data were obtained from the international Enroll-HD  , genotype-negative (people who were at risk, but tested negative), and family control subsamples (who were never at genetic risk but are part of an HD-affected family) (see Table 1 for frequency data).
To evaluate replicability, we also extracted data for the next two were lower due to some individuals not participating in second and third annual assessments.

Measures
The PBA-s is the recommended screening tool for behavioral symptoms in HD (McNally et al., 2015). It comprises an 11-item semistructured interview describing HD-related mental health symptoms and behavioral difficulties (depression, anxiety, irritability, aggression, apathy, obsessive-compulsive behaviors, perseveration, paranoid thinking/delusions, hallucinations, and disorientation). The scale is administered by a trained interviewer, who rates items on 5-point scales for severity (0 = absent to 4 = severe) and frequency (0 = never or almost never to 4 = daily/almost daily for most or all of the day). Overall item scores are calculated by multiplying frequency and severity, with scores ranging from 0 to 16. Item scores of 2 or higher indicate at least "mild" presence of that symptom. For our analyses, we used the presence or absence of symptoms for the 11 symptom domains (0 = not present, 1 = present).
We assigned participants to the manifest HD, premanifest HD, genotype-negative, or family control subsamples, and subdivided the manifest group into five subgroups based on Total Functional Capacity (TFC) scale scores (Shoulson & Fahn, 1979). This is a frequently used assessment of function in HD (Paulsen et al., 2010).
Like the PBA-s, the TFC scale is completed via a brief interview in which the pwHD is assessed for functional abilities around occupation, finances, domestic chores, activities of daily living, and care needs, with scores on each item ranging from 0 ("unable") to 3 ("normal").
Item scores are summed, with possible totals ranging from 0 to 13.
Higher scores indicate higher capacity for functioning. Scores from 11 to 13 represent Stage 1 (least severe); 7-10 represent Stage 2; 3−6 represent Stage 3; 1−2 represent Stage 4; and 0 represents Stage 5 (most severe). Therefore, in total, we used eight subsamples: manifest HD Stages 1 through to 5, premanifest HD, genotype-negative, and family control. HD stage is reconfirmed independently at each study visit. For subsample sizes at the three PBA-s administration times, see Tables 2-4.

Data analysis
The analysis comprised two stages. First, we evaluate overall effects for the associations between the eight HD subsamples (variable 1; eight levels; categorical) and the presence or absence of each of the PBAs indices (variable 2; two levels; dichotomous/categorical). Second, we assess where the specific differences lie between the eight groups in terms of the presence or absence of each of the PBA-s indices.
First, to assess overall effects, we report 33 chi-square tests of association (Monte Carlo test based on 10,000 randomized samples with a 99% confidence interval), evaluating HD subgroup differences for 11 PBA-s indices by three administration points, using Times 2 and 3 to assess the replicability of findings from Time 1. When the observed value for cells was less than 5, we report the chi-square statistic and statistical significance using the Fisher-Freeman-Halton exact test (Freeman & Halton, 1951). As the accuracy of statistical significance level in chi-square is vulnerable to sample size, we assessed the importance of the association using effect sizes for chi-square (Kim, 2017).
With smaller contingency tables, the tendency is to report the Cramer's there is no standardized guidance on Cramer's V. Instead, Cohen's w can be calculated (w = Cramer's V × square root(k -1), where k is the number of whichever is smaller of rows/columns) (Cohen, 1988;Sheskin, 2000). The magnitude of the effect size of w can be categorized with w ≥ .50 considered "large," .3 ≤ w < .5 "moderate," and .1 ≤ w < .3 "small" (Cohen, 1988;Sheskin, 2000). To ensure that overall associations were meaningful, we used the criterion of at least a moderate TA B L E 1 Sample sizes by total and subsamples with gender and mean age, motor score, CAG, and mean age of formal diagnosis (for manifest HD group only) statistics for the three administration times       Note: This type of analysis is not reported often. Consequently, to illustrate the analytic process, this note describes the apathy outcomes as an example. This table shows post hoc comparisons for apathy by subsample at administration time 1. The negatively adjusted residual z-scores are seen to significantly differ from the null hypotheses for the family control, genotype-negative, and premanifest subsamples, indicating significantly lower apathy from the null hypothesis. The positively adjusted residual z-scores also significantly differ from the null hypotheses for the Stages 2-5 HD subsamples, indicating significantly higher apathy. Only the Stage 1 HD subsample did not significantly differ from the null hypothesis.          effect size (.3 ≤ w < .5). This is the minimum at which findings can be considered of practical significance (Cohen, 1988).
Second, to identify specific differences between the eight groups, we evaluated between-group differences in PBA-s symptom severity via post hoc comparisons between the eight HD subsamples for each chi-square. We quantified between-group differences based on variation from a null hypothesis of expected observations. This technique uses a multiple-regression approach to analyze the differences between cells, using adjusted residual z-scores for accounting for the overall sample size, and variation due to that sample size (Beasley & Schumacher, 1995;García-Pérez & Núñez-Antón, 2003). Typically, a zscore of ±1.96 shows a statistically significant difference between cells at p < .05. Accordingly, we calculated a further chi-square for each post hoc comparison by squaring the adjusted residual z-score, and calculating the significance value using the SPSS 25 chi-square function with 1 degree of freedom for each comparison of each group. As we con-

RESULTS
Tables 2-4 show the percentage of each mental health symptom present (+) and absent (-) by subsample, providing chi-square, effect size, and post hoc comparison statistics (Table 2 shows Time 1;   Table 3 shows Time 2; Table 4 shows Time 3). For apathy, obsessivecompulsive behaviors, and disorientation at each administration, a significant difference of medium effect was found (a minimum at which the findings are considered to be of practical significance).
The post hoc comparisons show a broad pattern of significantly higher and lower differences from the null hypothesis of expected observations. For both apathy and obsessive-compulsive symptoms, a significantly higher frequency from expected observations was seen across administrations for the Stages 2-5 HD groups. Furthermore, a significantly lower frequency of apathy and obsessive-compulsive symptoms was seen in the family controls, genotype-negative, and premanifest groups across administrations (and at Stage 1 only for apathy).
For disorientation, significantly higher frequency from expected observations was seen within the Stage 3-5 HD subsamples. Furthermore, broadly, where there was significantly lower frequency of disorientation from expected observations, these tended to be within family controls, genotype-negative, premanifest, and Stages 1 and 2 of HD.
There are exceptions to these findings. Those with Stage 5 HD did not significantly differ from the expected observations for apathy and obsessive-compulsive symptoms at administration 3. Those with Stage 2 HD did not significantly differ in disorientation from expected observations at administration 1, and neither did those with Stage 1 or 2 HD at administration 3.
Finally, we considered changes in the presence of symptoms for the sample who provided responses across the three time periods using repeated measures analysis of variance. This method is an appropriate statistical technique for analyzing dichotomous outcome data where the degrees of freedom are greater than 40 (Lunney, 1970).

DISCUSSION
In this study, we examined psychological symptoms via PBA-s items between people at HD Stages 1-5, and HD family members who do not carry the gene expansion. This enabled evaluation of the frequency of symptoms throughout the disease course, and identification of symptoms that also occur in noncarriers (family controls and genotype-negative) within HD families. Clarifying these differences has important implications for psychological interventions in pwHD, and for supporting other people within HD-affected families.
In our study, people with later-stage HD (Stages 2-5) typically showed higher levels of apathy, while the family control, genotype-negative, and premanifest subsamples showed lower levels. Recent research has identified apathy to be associated with progressive atrophy of the thalamus among pwHD and loss of gray matter within the corticosubcortical network (Martínez-Horta et al., 2018), indicating a neural basis for the higher prevalence of apathy in later-stage HD.
People with later-stage HD (2-5) also had higher obsessivecompulsive symptoms than the premanifest and two noncarrier groups (family controls and genotype-negative). This suggests that obsessivecompulsive behaviors are also associated with HD progression, potentially related to increasing orbitofrontal and striatal dysfunction over time (Anderson et al., 2011;Nakao et al., 2014;Oosterloo et al., 2019).
Consideration of the potential role of medication and comorbidities may be important when judging the relevance of obsessive-compulsive behaviors in HD, however, as such symptoms may result from these factors rather than from progression. It is also clinically important to consider the difference between obsessive-compulsive behaviors and perseverative behaviors stemming from executive function changes (Oosterloo et al., 2019). While these may appear externally similar (repetitive behaviors), clearly potential treatment routes would differ depending on cause.
Finally, disorientation was also elevated for the later stages of the manifest subsample (predominantly stages 3-5), highlighting that this symptom may emerge later in the disease course than obsessivecompulsive behaviors and apathy, as cognition deteriorates significantly. Disorientation emerging as a key symptom in HD progression is concordant with prior findings of apathy, disorientation, and perseveration together forming an apathy subscale for the PBA-s (Callaghan et al., 2015). The neurological basis of disorientation generally appears less well-studied than the basis of apathy and obsessive-compulsive symptoms. However, one recent study (Lemoine et al., 2021) linked temporal disorientation with cell atrophy in the striatum (caudate and putamen), suggesting differential progression of HD-related disorientation with greater temporal than spatial difficulties emerging over time. This provides one potential neurobiological mechanism for the differentiation between the manifest and three remaining subsamples.
Importantly, significant differences in symptom frequency between pwHD (manifest and premanifest) and noncarriers (family controls and genotype-negative) were only found for three indices of the PBA-s, and not for the remaining eight (depression, suicidal ideation, anxiety, irritability, aggression, perseveration, paranoia, and hallucinations).
This supports previous findings that a degree of psychological distress in various forms is shared between carriers and noncarriers across HD-affected families (Achenbach & Saft, 2021;Maltby et al., 2021). Descriptions of psychosocial contributions to HD-related distress may support this interpretation, as both carriers and noncarriers may experience intense anxiety and distress relating to changed familial narratives, disrupted interpersonal dynamics, grief, and lost plans for the future (Berrios et al., 2002;Brouwer-DudokdeWit et al., 2002;Tibben et al., 1997;Yu et al., 2019). Our findings demonstrate that some key clinical psychological symptoms of HD are shared to a similar degree by nonmanifest groups, concordant with these previous findings.

Clinical implications and future research
These findings highlight key psychological changes as HD progresses, and demonstrate the importance of considering apathy, disorientation, and obsessive-compulsive symptoms in the clinical management of pwHD. There is a clear need for strategies to mitigate against the potential negative physical health and psychological effects of these difficulties. Further research into the neurological basis of disorientation and obsessive-compulsive behaviors in HD also appears critical.
The identification of similarities as well as differences between people with manifest HD and the premanifest, family control, and genotype-negative groups carries important clinical implications for supporting families affected by HD. There appears to be a shared level of distress across eight PBA-s domains, which promotes the importance of considering systemic well-being in the treatment of HD, and potentially considering family-level interventions or some difficulties.
Maintenance of carer well-being is also crucial due to the key role they play in supporting pwHD. Future research might explore potential systemic contributions to HD-related distress, alongside the more familiar impacts of physical and cognitive changes.

Strengths and limitations
We used a large international data set and established measures with strong psychometric properties to evaluate specific clinical symptoms relating to psychological well-being in pwHD across the disease course, and in comparison to additional HD-related populations.
This enabled us to both understand HD symptoms as the condition progresses and evaluate psychological difficulties found across HD families. We also examined these data across three timepoints and the findings evidenced high stability in our large sample, indicating robust results.
In terms of limitations, we did not examine data regarding medication use among participants-as noted, this may be of particular relevance regarding obsessive-compulsive symptoms. However, our findings concur with a robust literature supporting apathy, obsessivecompulsiveness, and disorientation as key psychological symptomatology in HD, including proposed neurobiological mechanisms. It is also challenging to measure psychological symptoms in HD; worsening anosognosia over time can impair validity of self-report (Gunn et al., 2020), and a lack of professional consensus around some mental health constructs, such as irritability, may reduce interrater reliability (Simpson et al., 2019). However, the consistency of our findings across timepoints and the consistency with other psychometric and neurobiological findings demonstrate an empirical consensus.
Importantly, those with the most advanced HD and poorest psychological well-being are unlikely to be well-represented in the Enroll-HD data set, due to access issues, deterioration in motivation, and escalating cognitive and behavioral difficulties associated with the later stages that complicate or prevent research participation. Additionally, those attending clinics regularly for monitoring are likely to receive earlier and more consistent support. Consequently, those with better psychological well-being and more support may be better represented.
However, this would likely reduce rather than enhance differences between the manifest group and the other subsamples, so this does not detract from the reported findings but raises the possibility that for some, the identified difficulties may arise earlier in the disease course than indicated by our results.
Finally, it was not possible to meaningfully compare differences between mental health symptoms among people in HD-affected families and controls from non-HD families, because the latter are not available in the data set (and generic prevalence data may not adequately take into account key demographic variables known to contribute to well-being). However, these comparisons will be crucial to demonstrate specific impacts of living in HD-affected families on people who do not carry the gene, compared to equivalent groups not affected by HD. This is an important subject for future study, although beyond the scope of the current analysis.

CONCLUSION
In conclusion, this study identifies distinctive mental health symptoms among people with later-stage manifest HD, with apathy and obsessive-compulsive behaviors emerging around stage 2 and disorientation around stage 3. This highlights important targets for clinical monitoring and intervention as HD progresses, as well as identifying potential psychological symptoms experienced in other members of HD families.

ACKNOWLEDGMENTS
Enroll-HD is a clinical research platform and longitudinal observational study for HD families intended to accelerate progress toward therapeutics; it is sponsored by the Cure HD Initiative Foundation.
Enroll-HD would not be possible without the vital contribution of the research participants and their families (https://www.enroll-hd.org/ acknowledgments/).

CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from Enroll-HD (Enroll-HD, RRID:SCR_023300). Restrictions apply to the availability of these data, which were used under license for this study.